¹Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis
²Department of Neurology & Neurological Sciences, Stanford University, Stanford, California
³The Emmes Corporation, Rockville, Maryland
⁴Department of Neurology, Northwestern University, Chicago, Illinois
⁵Department of Neurology, Emory University, Atlanta, Georgia
⁶Minnesota Epilepsy Group, Saint Paul
⁷Department of Neurology, University of Southern California, Los Angeles
⁸University of Cincinnati, Cincinnati, Ohio
⁹Neurology, Columbia University, New York, New York
¹⁰Department of Neurology, University of Washington, Seattle
¹¹Department of Psychiatry, University of Wisconsin at Madison, Madison
¹²Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
¹³Department of Neurological Surgery, University of Washington, Seattle

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Key Points

Question What is the extent of drug exposure via breastfeeding in infants whose mothers are receiving antiepileptic drug therapy?

Findings In this prospective cohort study, the median percentage of infant-to-mother concentration for 7 antiepileptic drugs ranged from 0.3% to 44.2% in 164 infant-mother concentration pairs. For infants with mothers receiving lamotrigine therapy, infant concentrations were associated with maternal concentrations.

Meaning In this study, the overall drug exposure was low in infants who were breastfed by mothers with epilepsy who were receiving antiepileptic drug therapy, and the findings add further support to breastfeeding by these mothers.

Abstract

Importance There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy.

Objective To provide direct, objective information on antiepileptic drug exposure through breast milk.

Design, Setting, and Participants This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks’ gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019.

Exposures Antiepileptic drug exposure in infants who were breastfed.

Main Outcomes and Measures The percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle.

Results A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P < .001) but not levetiracetam concentration in infants.

Conclusions and Relevance Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

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Article Information

Accepted for Publication: October 11, 2019.

Corresponding Author: Angela K. Birnbaum, PhD, Department of Experimental and Clinical Pharmacology, College of Pharmacy, Room 463, 717 Delaware St SE, University of Minnesota, Minneapolis, MN 55414 (birnb002@umn.edu).

Published Online: December 30, 2019. doi:10.1001/jamaneurol.2019.4443

Author Contributions: Drs Birnbaum and Karanam had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Birnbaum, Meador, May, Pennell.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Birnbaum, Karanam, Penovich, Brown, May.

Critical revision of the manuscript for important intellectual content: Birnbaum, Meador, Brown, May, Gerard, Gedzelman, Penovich, Kalayjian, Cavitt, Pack, Miller, Stowe, Pennell.

Statistical analysis: Birnbaum, Karanam, Brown, May.

Obtained funding: Meador, Pack, Pennell, Birnbaum.

Administrative, technical, or material support: Cavitt, Pack, Miller, Pennell.

Supervision: Birnbaum, Meador, May, Kalayjian, Cavitt, Pennell.

Conflict of Interest Disclosures: Dr Birnbaum has received research support from the National Institutes of Health, Epilepsy Foundation, Supernus Pharmaceuticals, and Veloxis Pharmaceuticals and is also a coinventor of a patent for intravenous carbamazepine (Lundbeck Pharmaceuticals). Dr Meador has received research support from the National Institutes of Health and Sunovion Pharmaceuticals and travel support from UCB Pharma; the Epilepsy Study Consortium pays Dr Meador’s university for his research consultant time for Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals. Dr Gerard received research support from Sage Pharmaceuticals and Sunovion Pharmaceuticals and received speaker and travel funds from UCB Pharma. Dr Penovich has served on speakers’ bureaus for Eisai, Sunovian, GW Pharmaceuticals, Aquestive Therapeutics, and UCB. Dr Cavitt received research support from the National Institute of Neurological Disorders and Stroke and GW Pharmaceuticals. Dr Pack received royalties for the website UpToDate. Dr Miller has received grant and research support from the National Institutes of Health, Medtronic, the US Centers for Disease Control and Prevention, SK Biopharmaceuticals, Eisai, and Xenon Pharma and has a financial relationship with Therma Neurosciences Inc involving advisory board participation and patents. Dr Pennell has received research support from the National Institutes of Health and the Epilepsy Foundation and honoraria and travel support from American Epilepsy Society, American Academy of Neurology, Epilepsy Foundation, National Institutes of Health, and academic institutions for continuing medical education lectures. No other disclosures were reported.

Funding/Support: This work was supported by National Institute of Neurological Disorders and Stroke and National Institute of Child Health and Development (grants U01-NS038455 [Drs Meador and Pennell]), U01-NS050659 [Dr May], and 2U01-NS038455 [Drs Meador, Pennell, and May]).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Authors: MONEAD Investigator Group: Executive Committee: Kimford J. Meador, MD (Stanford University, Stanford, California, Multiple principal investigator and executive committee director); Page B. Pennell, MD (Harvard University, Brigham & Women’s Hospital, Boston, Massachusetts, multiple principal investigator and codirector of semiology core); Ryan May, PhD (the Emmes Corporation, multiple principal investigator and director of data and statistical center); Angela Birnbaum, PhD (University of Minnesota, Minneapolis, director of pharmacokinetics core); Morris J. Cohen, EdD (Pediatric Neuropsychology International, codirector of neuropsychology center); Maurice Druzin, MD (Stanford University, Stanford, California, codirector of obstetrics [OB] core); Richard Finnell, PhD (Baylor College of Medicine, Houston, Texas, consultant on teratogenicity); Jacqueline French, MD (New York University, New York, codirector, semiology core); Gregory Holmes, MD (University of Vermont, consultant); David W. Loring, PhD (Emory University, Atlanta, Georgia, codirector, neuropsychology center and chair, publications committee); Frederick T. McElrath, MD (Harvard University, Brigham & Women’s, Boston, Massachusetts, codirector of OB core); Lorene Nelson, PhD (Stanford University, Stanford, California, consultant); Zachary Stowe, MD (University of Wisconsin, director of psychiatric core); Linda Van Marter, MD (Harvard University, Brigham & Women’s, Boston, Massachusetts, director of neonatal core); Peter Wells, PharmD (University of Toronto, consultant); Mark Yerby, MD (Oregon Health Sciences University, consultant); Eugene Moore, BS (Emory University, Atlanta, Georgia, multisite research project manager). Data and Statistical Center: Ryan May, PhD (The Emmes Corporation, multiple principal investigator and director of data and statistical center); Dominic Ippolito, MS (The Emmes Corporation, project manager), Anjali Nair, MS (The Emmes Corporation, data manager/protocol monitor), Becky Ayre, BS (The Emmes Corporation, data manager/protocol monitor), Julia Skinner, MS (The Emmes Corporation, SAS programmer), Lisa Davis, BA (The Emmes Corporation, administrative coordinator), Linda Hendrickson (The Emmes Corporation, administrative coordinator), Nilay Shah, MD (The Emmes Corporation, medical monitor), Brenda Leung, BS (The Emmes Corporation, programmer analyst), Michelle Arias, BA (The Emmes Corporation, clinical systems analyst). MONEAD Site Investigators: Augusta University: Suzanne Strickland, MD (Augusta University, site principal investigator); Erin Latif, MD (Augusta University, OB co-investigator); Yong Park, MD (Augusta University, OB co-investigator); Delmaris Acosta-Cotte, MA (Augusta University, site neuropsychologist); Patty Ray, PhD (Augusta University, research assistant); Columbia University: Alison Pack, MD (Columbia University, site principal investigator); Kirsten Cleary, MD (Columbia University, OB co-investigator); Joyce Echo, PhD (Columbia University, site neuropsychologist); Annette Zygmunt, PhD (Columbia University, site neuropsychologist); Camilla Casadei, BA (Columbia University, research assistant); Emory University, Atlanta, Georgia: Evan Gedzelman, MD (Emory University, Atlanta, Georgia, site principal investigator); Mary Dolan, MD (Emory University, Atlanta, Georgia, OB co-investigator); Kim Ono, PhD (Emory University Children’s Healthcare of Atlanta, Atlanta, Georgia, site neuropsychologist); Donald Bearden, PhD (Emory University Children’s Healthcare of Atlanta, Atlanta, Georgia, site neuropsychologist); Christine Ghilian, PhD (Emory University Children’s Healthcare of Atlanta, Atlanta, Georgia, site neuropsychologist); Diane Teagarden, MSN (Emory University, Atlanta, Georgia, co-investigator); Melanee Newman, RN (Emory University, Atlanta, Georgia, research assistant); Geisinger Clinic: Paul McCabe, MD (Geisinger Clinic, site principal investigator); Michael Paglia, MD (Geisinger Clinic, OB co-investigator); Cora Taylor, PhD (Geisinger Clinic, site neuropsychologist); Rosemarie Delucca, RN (Geisinger Clinic, research assistant); Kristina Blessing MSW (Geisinger Clinic, research assistant); Harvard University, Boston, Massachusetts, and affiliated hospitals: Page Pennell, MD (Brigham & Women’s Hospital, Boston, Massachusetts, site principal investigator); Frederick T. McElrath, MD (Brigham & Women’s Hospital, Boston, Massachusetts, OB co-investigator); Linda Van Marter, MD (Brigham & Women’s Hospital, Boston, Massachusetts, director of neonatal core); Katrina Boyer, PhD (Boston Children’s Hospital, Boston, Massachusetts, site neuropsychologist); Ellen Hanson, PhD (Boston Children’s Hospital, Boston, Massachusetts, site neuropsychologist); Amy Young, PsyD (Boston Children’s Hospital, Boston, Massachusetts, site neuropsychologist); Paige Hickey, BS (Boston Children’s Hospital, Boston, Massachusetts, site psychometrist); Jolie Strauss, MA (Boston Children’s Hospital, Boston, Massachusetts, site psychometrist); Hayley Madeiros, BS (Boston Children’s Hospital, Boston, Massachusetts, site psychometrist); Li Chen, BA (Brigham & Women’s Hospital, Boston, Massachusetts, research assistant); Stephanie Allien, PAC (Brigham & Women’s Hospital, Boston, Massachusetts, research physician’s assistant); Yvonne Sheldon, RN (Brigham & Women’s Hospital, Boston, Massachusetts, neonatal research nurse); Taylor Weinau, BS (Brigham & Women’s Hospital, Boston, Massachusetts, OB research assistant). Henry Ford Hospital, Detroit, Michigan: Gregory L. Barkley, MD (Henry Ford Hospital, Detroit, Michigansite principal investigator); Marianna Spanaki-Varelas, MD PhD (Henry Ford Hospital, Detroit, Michigan, OB co-investigator); Andrea Thomas, MS (Henry Ford Hospital, Detroit, Michigan, site neuropsychologist); Jules Constantinou, MD (Henry Ford Hospital, Detroit, Michigan, co-investigator); Nazin Mahmood, MD (Henry Ford Hospital, Detroit, Michigan, co-investigator); Vibhangini Wasade, MD (Henry Ford Hospital, Detroit, Michigan, co-investigator); Shailaja Gaddam, MD (Henry Ford Hospital, Detroit, Michigan, co-investigator); Andrew Zillgitt, DO (Henry Ford Hospital, Detroit, Michigan, co-investigator); Taimur Anwar, MD (Henry Ford Hospital, Detroit, Michigan, OB co-investigator); Carla Sandles, CCRP (Henry Ford Hospital, Detroit, Michigan, research assistant); Theresa Holmes, BA (Henry Ford Hospital, Detroit, Michigan, research assistant); Johns Hopkins University, Baltimore, Maryland: Emily Johnson, MD (Johns Hopkins University, Baltimore, Maryland, site principal investigator); Gregory Krauss, MD (Johns Hopkins University, Baltimore, Maryland, prior site principal investigator) Shari Lawson, MD (Johns Hopkins University, Baltimore, Maryland, OB co-investigator); Alison Pritchard, PhD (John Hopkins University, Baltimore, Maryland, site neuropsychologist); Matthew Ryan, MS (John Hopkins University, Baltimore, Maryland, site neuropsychologist); Pam Coe, MS (John Hopkins University, Baltimore, Maryland, research assistant); Minnesota Epilepsy Group: Patricia Penovich, MD (Minnesota Epilepsy Group, St Paul, site principal investigator); Katie Reger, PhD (Minnesota Epilepsy Group, St Paul, site neuropsychologist); Jenny Pohlman, MBS (Minnesota Epilepsy Group, St Paul, research assistant); Alisha Olson, RN (Minnesota Epilepsy Group, St Paul, research assistant); New York University: Jacqueline French, MD (New York University, New York, site principal investigator); William Schweizer, MD (New York University, New York, OB co-investigator); Chris Morrison, PhD (New York University, New York, site neuropsychologist); William MacAllister, PhD (New York University, New York, site neuropsychologist); Tobi Clements, BA (New York University, New York, research assistant); Northwell Health: Sean Hwang, MD (Northwell Health, site principal investigator); Hima Bindu Tam, MD (Northwell Health, OB co-investigator); Yael Cukier, PhD (Northwell Health, site neuropsychologist); Erica Meltzer, MD (Northwell Health, site neuropsychologist); Jacqueline Helcer PhD (Northwell Health, site neuropsychologist); Connie Lau, MS (Northwell Health, research assistant; Northwestern University, Chicago, Illinois: Elizabeth Gerard, MD (Northwestern University, site principal investigator); William Grobman, MD (Northwestern University, Chicago, Illinois, OB co-investigator); Joseph Coda, PsyD (Northwestern University, Chicago, Illinois, site neuropsychologist); Emily Miller, MD (Northwestern University, Chicago, Illinois, OB co-investigator); Irena Bellinski, RN (Northwestern University, Chicago, Illinois, research assistant); Elizabeth Bachman, MPH (Northwestern University, Chicago, Illinois, research assistant); Stanford University, Stanford, California: Kimford Meador, MD (Stanford University, Stanford, California, site principal investigator); Maurice Druzin, MD (Stanford University, Stanford, California, OB co-investigator); Casey Krueger PhD (Stanford Healthcare, Stanford, California, site neuropsychologist); Jordan Seliger, MA (Stanford University,Stanford, California, research assistant); University of Alabama at Birmingham: Jennifer DeWolfe, DO (University of Alabama at Birmingham, site principal investigator); John Owen, MD (University of Alabama at Birmingham, OB co-investigator); Matthew Thompson, PsyD (University of Alabama at Birmingham, site neuropsychologist); Cheryl Hall, LPN (University of Alabama at Birmingham, research assistant); University of Arizona: David Labiner, MD (Arizona Health Sciences Center, Tucson, site principal investigator); James Maciulla, MD (University of Arizona, Tucson, OB co-investigator); Jennifer Moon, PsyD (University of Arizona, Tucson, site neuropsychologist); Kayla Darris, BA (University of Arizona, Tucson, research assistant); University of Cincinnati, Cincinnati, Ohio: Jennifer Cavitt, MD (University of Cincinnati, Cincinnati, Ohio, site principal investigator); Michael Privitera, MD (University of Cincinnati, Cincinnati, Ohio, co-investigator); Kellie Flood-Schaffer, MD (University of Cincinnati, Cincinnati, Ohio, OB co-investigator); George Jewell, PhD (University of Cincinnati, Cincinnati, Ohio, site neuropsychologist); Lucy Mendoza, CCRP (University of Cincinnati, Cincinnati, Ohio, research assistant); University of Miami, Miami, Florida: Enrique Serrano, MD (University of Miami, Miami, Florida, site principal investigator); Yasin Salih, MD (University of Miami, Miami, Florida, OB co-investigator); Christin Bermudez, PhD (University of Miami, Miami, Florida, site neuropsychologist); Michelle Miranda, PhD (University of Miami, Miami, Florida, site neuropsychologist); Naymee Velez-Ruiz, MD (University of Miami, Miami, Florida, co-investigator); Pedro Figueredo, MD (University of Miami, Miami, Florida, research assistant); University of Pittsburgh, Pittsburgh, Pennsylvania: Anto Bagic, MD (University of Pittsburgh, Pittsburgh, Pennsylvania, site principal investigator); Alexandra Popescu Urban MD (University of Pittsburgh, Pittsburgh, Pennsylvania, co-investigator); Satya Gedela, MD (University of Pittsburgh, Pittsburgh, Pennsylvania, co-investigator); Christina Patterson, MD (University of Pittsburgh, Pittsburgh, Pennsylvania, co-investigator); Arundhathi Jeyabalan, MD (University of Pittsburgh, Pittsburgh, Pennsylvania, OB co-investigator); Krestin Radonovich PhD (University of Pittsburgh, Pittsburgh, Pennsylvania, site neuropsychologist); Melissa Sutcliffe, PhD (University of Pittsburgh, Pittsburgh, Pennsylvania, site neuropsychologist); Susan Beers, PhD (University of Pittsburgh, Pittsburgh, Pennsylvania, site neuropsychologist); Carrie Wiles, MS (University of Pittsburgh, Pittsburgh, Pennsylvania, site neuropsychologist); Sandra Alhaj, BS (University of Pittsburgh, Pittsburgh, Pennsylvania, research assistant); University of Southern California: Laura Kalayjian, MD (University of Southern California, Los Angeles, site principal investigator); Alice Stek, MD (University of Southern California, Los Angeles, OB co-investigator); Sonia Perez, PhD (University of Southern California, Los Angeles, site neuropsychologist); Rachel Sierra, RC (University of Southern California, Los Angeles, research assistant); University of Washington: John W. Miller, MD (University of Washington, Seattle, site principal investigator); Jennie Mao, MD (University of Washington, Seattle, OB co-investigator); Vaishali Phatak PhD (University of Washington, Seattle, site neuropsychologist); Michelle Kim PhD (University of Washington, Seattle, site neuropsychologist); Andrea Cheng-Hakimian, MD (University of Washington, Seattle, co-investigator); Gina DeNoble MS (University of Washington, Seattle, research assistant); Wake Forest University Health Sciences, Winston-Salem, North Carolina: Maria Sam, MD (Wake Forest University Health Sciences, Winston-Salem, North Carolina, site principal investigator); Lamar Parker, MD (Wake Forest University Health Sciences, Winston-Salem, North Carolina, OB co-investigator); Melissa Morris MA (Wake Forest University Health Sciences, Winston-Salem, North Carolina, site neuropsychologist); Jessica Dimos, BS (Wake Forest University Health Sciences, Winston-Salem, North Carolina, research assistant); multisite: Danielle Miller, MA (project traveling neuropsychologist).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Meeting Presentation: This paper was presented as a poster at the American Epilepsy Society meeting; December 3, 2016; Houston, Texas.

Additional Contributions: The investigators thank the children and families who have given their time to participate in the MONEAD study. The authors thank all the members of the MONEAD study for their contributions. (These authors were compensated as part of the National Institutes of Health grant that funded this study.)

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